N-alkylbenzo(b)thieno [3,2-b]oxazin-2,4-diones

ABSTRACT

N-Alkenylbenzo[b]thieno[3,2-b]oxazin-2,4-diones, pro-drugs of cyclooxygenase and 5-lipoxygenase inhibitory N-alkenyl-3-hydroxybenzo[b]thiophene-2-carboxamide derivatives; pharmaceutical compositions comprising one or more of said pro-drugs and a pharmaceutical acceptable carrier; and the use of said pro-drugs to treat mammalian diseases arising from biological mediators formed in the mammalian body by cyclooxygenase and/or 5-lipoxygenase catalyzed reactions.

BACKGROUND OF THE INVENTION

This invention relates to pro-drugs of certain 3-hydroxybenzothiopheneswhich have a 2-enamido side chain. More particularly it relates tocyclic pro-drugs of N-alkenyl-3-hydroxybenzo[b]thiophene-3-carboxamideswhich exhibit cyclooxygenase and 5-lipoxygenase inhibitory action,pharmaceutical compositions thereof, and the use thereof to treatvarious mammalian diseases.

U.S. Pat. No. 4,760,086, issued Jul. 26, 1988, describes a large numberof N-alkenyl-3-hydroxybenzo[b]-thiophene-3-carboxamides of formula (I)##STR1## wherein each of X₁ -X₄, R and R¹ -R⁴ are broadly defined aslower alkyl, aryl, heteroaryl, lower cycloalkyl, benzyl, lower alkenylor lower alkynyl any of which may be substituted by a variety ofsubstituents.

Said compounds are disclosed to be effective inhibitors ofcyclooxygenase and 5-lipoxygenase and, therefore, of value in thetreatment of inflammation, pain, fever and other prostaglandin and/orleukatriene mediated diseases.

U.S. Pat. No. 4,656,265, issued Apr. 7, 1987, describes cyclic pro-drugsof non-steroidal anti-inflammatory oxicams. In said pro-drugs, theparent oxicams are chemically modified to form a fused 1,3-oxazine ringsystem, which, in vivo, is cleaved to restore the parent compound.

SUMMARY OF THE INVENTION

This invention provides compounds of formula (II) below ##STR2## whereinX is hydrogen, trifluoromethyl, fluoro, chloro, lower alkyl, loweralkoxy, lower alkylthio, phenyl or 2,4-difluorophenyl;

each of R¹ and R² is hydrogen, phenyl, substituted phenyl wherein thesubstituent is chloro, fluoro, lower alkyl, lower alkoxy, loweralkylthio or hydroxy; furyl, thienyl, substituted thienyl wherein thesubstituent is lower alkyl, chloro or fluoro; lower alkyl, chloro, loweralkoxycarbonyl; furyl or pyrryl, which compounds are cyclic pro-drugs ofcompounds of formula (I) above wherein each of R, R¹ and R⁴ is hydrogen.

The substituents (R¹ and R²) on the double bond can be syn, anti or amixture of both. Thus, in formula (II), substituents R¹ and R² areindicated as being attached to the double bond by wavy lines. Thisrepresentation is intended to depict all forms of the isomers of formula(II) compounds. The individual isomers of formula (II) compounds can beprepared by starting with the appropriate isomer of the requisiteformula (I) reactant. Alternatively, the isomers can be separated from amixture thereof by known methods such as chromatography.

Formula (II) compounds, unlike the parent compounds of formula (I), arenot enolic acids and, therefore, show less gastric irritation than dothe parent compounds. Following their administration to a mammal,including a human, formula (II) compounds release the parent compound bysome metabolic process.

Also included in this invention are pharmaceutical compositions suitablefor administration to a mammal, including a human, said compositionscomprising a pharmaceutically acceptable carrier and a cyclooxygenaseand/or 5-lipoxygenase inhibiting amount of a compound of formula (II);and a method of treating diseases arising from biological mediatorsformed by cyclooxygenase and/or 5-lipoxygenase catalyzed reactions in amammalian body which comprises administering to a mammal in need of suchtreatment a cyclooxygenase and/or 5-lipoxygenase inhibiting amount of acompound of formula (II).

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (II) are prepared by reacting a compound of formula(I) wherein each of R, R¹ and R⁴ is hydrogen with phosgene as cyclizingagent in a reaction-inert solvent in the presence of an acid bindingagent at a temperature of -70° C. to +50° C.

Suitable reaction-inert solvents, i.e., solvents which do not react withreactants or products in such a manner as to reduce yield of the desiredproduct, are halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such asethyl or isopropyl ether, dioxane and tetrahydrofuran; acyclichydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbonssuch as benzene, toluene and xylene; cyclic hydrocarbons such ascyclopentane and cyclohexane; ethyl acetate, dimethylformamide,acetonitrile and dimethylsulfoxide. Preferred solvents are methylenechloride, ethyl ether, tetrahydrofuran and ethyl acetate.

Cyclizing agents other than phosgene can, of course, be used.Representative of such agents are those of the formula Y-COCl where Y is(C₁₋₄)alkoxy, phenoxy, benzyloxy or trichloromethoxy. Phosgene is,however, the preferred cyclizing agent.

Suitable acid binding agents for use in the invention process are thosebasic compounds which will bind the hydrogen chloride formed in thereaction but will not form an unwanted by-product with the reagentY-COCl or compounds of formula (I) under the conditions employed.Examples of suitable acid binding agents include tertiary amines such asthe trialkylamines having from 3 to 30 carbon atoms, dialkyl aryl aminesand alkyl diaryl amines having 8 to 30 carbon atoms, aralkyl dialkylamines having from 9 to 30 carbon atoms, N-alkyl heterocyclic amineshaving from 6 to 25 carbon atoms; alkali metal or alkaline earthcarbonates or bicarbonates, and alkaline earth oxides or hydroxides.Particularly preferred acid binding agents are sodium bicarbonate,calcium carbonate, calcium oxide, N,N-dimethylaniline,N-methylmorpholine and N-methylpiperidine. Most particularly preferredis triethylamine.

In theory the cyclizing agent, Y-COCl, and the starting compound offormula (I) are required in equimolar amounts to form the desired,respective products of formula (II). In practice, however, an excess ofthe cyclizing agent is ordinarily employed in order to ensure completionof reaction and to minimize the formation of unwanted by-products.Typically, a molar excess of from about 1 to 10 times is employed withgood results.

The reaction can be conducted over a temperature range of from about-70° C. to +50° C. The favored temperature range is from -30° C. to 30°C. The preferred temperature range is from -10° C. to 25° C. with 0° C.to 25° C. being the especially preferred range.

The reaction is generally complete in less than four hours and theproducts isolated and purified by standard methods known to thoseskilled in the art.

The starting materials of formula (I) are available by proceduresdescribed in U.S. Pat. No. 4,706,086. The cyclizing agents arecommercially available as are the acid-binding agents.

The cyclic prodrugs of this invention are evaluated for theiranti-inflammatory activity according to known methods by administeringmultiple oral doses in model tests such as the rat foot edema test, ratadjuvant-induced arthritis test or phenylbenzoquinone-induced writhingtest in mice, as described in U.S. Pat. No. 4,760,086 and elsewhere inthe literature; see e.g., C. A. Winter, in "Progress in Drug Research"edited by E. Jucker, Birkhauser Verlag, Basel, Vol. 10, 1966, pp.139-192.

In comparison with the parent compounds of formula (I), the novelpro-drugs of formula (II) are found to have markedly reduced ability toinhibit prostaglandin synthesis from arachidonic acid in tests carriedout by a modification of the method of T. J. Carty et al.,Prostaglandins, 19, 51-59 (1980). In the modified procedure cultures ofrat basophilic leukemic cells (RBL-1), prepared by the method ofJakschik et al., ibid, 16, 733 (1978), are employed in place of mousefibroblast (MC5-5) and rabbit synovial cell cultures. Thus, theinvention compounds themselves are relatively inactive asanti-inflammatory agents, but they give rise to an activeanti-inflammatory compound upon hydrolysis in vivo. Since the compound(II) is not an enolic acid and it is known that the hydrolysis takesplace after the pro-drug leaves the stomach, they will significantlyreduce the gastric irritation caused by oral administration of theparent enolic oxicams.

On a molar basis, the present pro-drugs are generally dosed at the samelevel and frequency as the parent from which they are derived. However,the non-enolic nature of the present compounds will generally permithigher tolerated doses, when such higher dosage is required in thecontrol of inflammation.

In general, the invention compounds are administered via either theoral, parenteral or topical routes in doses ranging from about 0.01 mgto 150 mg per kg of body weight, although variations will necessarilyoccur depending upon the weight and condition of the subject beingtreated and the particular route of administration chosen. However, adosage level that is in the range of from about 0.5 mg to about 7.5 gper patient per day is most desirably employed. Nevertheless, variationsmay occur depending upon the species of animal being treated and itsindividual response to said medicament, as well as on the type ofpharmaceutical formulation and the time period and interval at whichsuch administration is carried out. In some instances, dosage levelbelow the lower limit of the aforesaid range may be more than adequate,while in other cases still larger doses may be employed without harmfulside effects provided that such higher dose levels are first dividedinto several smaller doses for administration throughout the day.

The present pro-drugs are also formulated in the same manner andadministered by the same routes as the parent compounds as described inU.S. Pat. No. 4,760,086. The preferred route of administration is oral,thus taking particular advantage of the nonenolic nature of the presentcompounds.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium sterate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in this connectionwould also include lactose or milk sugar as well as high molecularweight polyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes, and, if so desired, emulsifying and/or suspending agentsas well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions in either sesame orpeanut oil or in aqueous propylene glycol may be employed, as well assterile aqueous solutions of the corresponding water-soluble alkalimetal or alkaline-earth metal salts previously enumerated. Such aqueoussolutions should be suitably buffered, if necessary, and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular solutions are especially suitable for intravenous,intramuscular and subcutaneous injection purposes. Additionally, it isalso possible to administer the aforesaid compounds topically and thismay be preferably done by way of creams, salves, jellies, pastes,ointments and the like, in accordance with standard pharmaceuticalpractice.

This invention is still further illustrated by the following examples,which are not to be construed as imposing limitations upon the scopethereof. On the contrary, it is to be clearly understood that resort maybe had to various other embodiments, modifications and equivalentsthereof which readily suggest themselves to those skilled in the artwithout departing from the spirit of the present invention and/or thescope of the appended claims.

EXAMPLE 1N-[2-phenyl-2-(2-thienyl)ethenyl]-3-hydroxy-5-trifluoromethyl-benzo[b]thieno[3,2-b]oxazin-2,4-dione

3-Hydroxy-5-trifluoromethyl-N-[2-(2-thienyl)-2-phenylethenyl]benzo[b]thiophene-2-carboxamide(0.2 g, 0.448 mmole) was dissolved in 30 ml of dry methylene chlorideand cooled to 0° C. under nitrogen. Triethylamine (0.156 ml, 1.12 mmole)was added and the reaction mixture stirred at 0° C. for several minutes.This was followed by bubbling in excess of phosgene gas. The reactionmixture was then stirred at 0° C. for about 1 hour followed by warmingto room temperature at which point TLC analysis [CH₂ Cl₂ /hexane(2:1)]showed nearly complete consumption of starting material andformation of a single more polar product. The reaction was stirred atroom temperature for an additional 2 hours followed by gentle warming toremove excess phosgene. The reaction mixture was diluted with ethylacetate (200 ml) and washed with 2N HCl (2×100 ml), water (1×100 ml),brine and dried (Na₂ SO₄). Concentration of the ethyl acetate extract invacuo gave a total of 210 mg of dark yellow-brown oil which was purifiedon a silica gel column (CH₂ Cl₂), affording 0.17 g of light brown foamysolid. Recrystallization from toluene-hexane gave an orange-browncrystalline solid, m.p. 208°-210° C., comprising a mixture of isomers:high resolution mass spectra M⁺ =471.0225 calcd. for C₂₃ H₁₂ O₃ NS₂ F₃471.0212. IR GKBr 1700 and 1780 cm⁻¹.

EXAMPLE 2

Isomeric Forms of the Example 1 Product

The procedure of Example 1 was repeated but using as reactants theindividual isomers, identified as isomers A and B, of the Example 1starting material. The isomer A product melted at 180°-182° C.; theisomer B product at 219°-221° C.

EXAMPLE 3

In like manner, following the procedure of Example 1 mutis mutandi, thecompounds listed below are prepared.

    ______________________________________                                         ##STR3##                                                                     X            R.sup.1        R.sup.2                                           ______________________________________                                        H            CH.sub.3       CH.sub.3                                          H            2-thienyl      phenyl                                            5-CF.sub.3   2-thienyl      2-thienyl                                         5-CF.sub.3   2-(5-CH.sub.3 thienyl)                                                                       phenyl                                            5-CF.sub.3   C.sub.6 H.sub.5                                                                              C.sub.6 H.sub.5                                   4-CF.sub.3   C.sub.6 H.sub.5                                                                              C.sub.6 H.sub.5                                   5-F          C.sub.6 H.sub.5                                                                              C.sub.6 H.sub.5                                   5-CH.sub.3   C.sub.6 H.sub.5                                                                              4-CH.sub.3 phenyl                                 5-CH.sub.3   C.sub.6 H.sub.5                                                                              C.sub.6 H.sub.5                                   5-CH.sub.3   3-Fphenyl      3-Fphenyl                                         4-CH.sub.3 O phenyl         phenyl                                            5-Cl         phenyl         phenyl                                            5-CF.sub.3   4-CH.sub.3 Ophenyl                                                                           phenyl                                            5-(2,4-F.sub.2 C.sub.6 H.sub.3)                                                            phenyl         phenyl                                            5-CH.sub.3 S 2-thienyl      phenyl                                            5-CF.sub.3   4-CH.sub.3 Ophenyl                                                                           4-CH.sub.3 Sphenyl                                6-CF.sub.3   phenyl         pyrryl                                            7-CF.sub.3   4-CH.sub.3 Sphenyl                                                                           2-furyl                                           5-CF.sub.3   4-HOphenyl     4-CH.sub.3 Sphenyl                                5-CF.sub.3   4-CH.sub.3 phenyl                                                                            4-CH.sub.3 phenyl                                 5-phenyl     phenyl         phenyl                                            5-CF.sub.3   4-OHphenyl     4-OHphenyl                                        ______________________________________                                    

I claim:
 1. A compound of the formula (II) ##STR4## wherein X ishydrogen, trifluoromethyl, fluoro, chloro, lower alkyl, lower alkoxy,lower alkylthio, phenyl or 2,4-difluorophenyl;each of R¹ and R² ishydrogen, phenyl, substituted phenyl wherein the substituent is chloro,fluoro, lower alkyl, lower alkoxy, lower alkylthio or hydroxy; furyl,thienyl, substituted thienyl wherein the substituent is lower alkyl,chloro or fluoro; lower alkyl, chloro, lower alkoxycarbonyl; furyl orpyrryl.
 2. A compound according to claim 1, said compound having theformula ##STR5## wherein each of X, R¹ and R² are as defined in claim 1.3. A compound according to claim 2 wherein X is hydrogen, lower alkyl ortrifluoromethyl; each of R¹ and R² is lower alkyl, phenyl, substitutedphenyl wherein the substituent is chloro, fluoro, hydroxy, lower alkylor lower alkoxy; thienyl; methyl thienyl; furyl or pyrryl.
 4. A compoundaccording to claim 3 wherein X is hydrogen.
 5. The compound according toclaim 4 wherein X is hydrogen and each of R¹ and R² is phenyl.
 6. Thecompound according to claim 4 wherein X is hydrogen; R¹ is phenyl and R²is 2-thienyl.
 7. A compound according to claim 3 wherein X istrifluoromethyl.
 8. The compound according to claim 7 wherein X istrifluoromethyl; and each of R¹ and R² is phenyl.
 9. The compoundaccording to claim 7 wherein X is trifluoromethyl; R¹ is phenyl and R²is 2-thienyl.
 10. The compound according to claim 3 wherein X is methyl;and each of R¹ and R² is phenyl.
 11. A pharmaceutically acceptablecomposition comprising a pharmaceutically acceptable carrier and acyclooxygenase and/or 5-lipoxygenase inhibiting amount of a compoundaccording to claim
 1. 12. A method for treating inflammatory diseases ina mammal arising from biological mediators selected from prostaglandinsand leukotrienes formed by cyclooxygenase and/or 5-lipoxygenasecatalyzed reactions in a mammalian body which comprises administering toa mammal in need of such treatment a cyclooxygenase and/or5-lipoxygenase inhibiting amount of a compound of formula ##STR6##wherein X is hydrogen, trifluoromethyl, fluoro, chloro, lower alkyl,lower alkoxy, lower alkylthio, phenyl or 2,4-difluorophenyl;each of R¹and R² is hydrogen, phenyl, substituted phenyl wherein the substituentis chloro, fluoro, lower alkyl, lower alkoxy, lower alkylthio orhydroxy; furyl, thienyl, substituted thienyl wherein the substituent islower alkyl, chloro or flouro; lower alkyl, chloro, loweralkoxycarbonyl; furyl or pyrryl.